Abstract
The successful treatment of oral squamous cell carcinoma (OSCC) depends on the treatment strategy. The prognosis is most often linked to the stage at initial presentation, but the effect of patient-related parameters on overall survival remains uncertain. In this study, 392 consecutive cases of OSCC seen between 2007 and 2013 at a single centre were analyzed retrospectively. Overall survival was assessed and univariate and multivariate Cox proportional hazards regression was used to identify associations between possible tumour-specific and patient-related variables and survival. The 5-year overall survival rate of the 392 patients (T stage 1–4) was 62.5%. Univariate analysis showed that sex, age, T stage, N stage, Union for International Cancer Control (UICC) stage, American Society of Anesthesiologists (ASA) status, operating time >400 min, and length of in-patient stay >15 days were significantly associated with overall survival (all P < 0.05). Tumour location, alcohol abuse, and smoking were found not to have a significant influence (all P > 0.05). Age, T, N, and M stages, UICC stage, residual tumour status, recurrence, ASA status, and operating time >400 min were found to have a significant influence on overall survival in the multivariate analysis (each P < 0.05). These findings confirm that postoperative survival does not depend only on tumour-related characteristics. ASA status needs to be considered in treatment planning, as it significantly predicts patient survival.
The survival time of patients affected by oral squamous cell carcinoma (OSCC) is dependent on a number of variables. Tumour-specific characteristics such as tumour location, tumour size, lymph node status, grading, resection margins, and perineural invasion are well known. Survival is also influenced by patient-related factors, such as physiological, psychological, social, and environmental conditions (American Society of Anesthesiologists (ASA) status, symptoms at presentation) and other interventional factors, e.g., immediate microsurgical reconstruction, operator-specific issues, resources, and length of in-patient stay.
The overall tumour stage is an important prognostic factor. Various studies have revealed that T1 and T2 stage lesions of the oral cavity are significantly more likely to have a disease-free interval than T3 and T4 stage lesions. A great influence on postoperative survival is seen when loco-regional lymph nodes are affected, with postoperative survival decreasing dramatically. A recent prospective randomized controlled trial revealed higher rates of overall and disease-free survival among patients with early-stage OSCC treated with an elective neck dissection. This suggests that elective neck dissection should be undertaken even at the initial T stages of cancer in order to detect possible occult lymph node metastasis, and that oral cancer should not be treated in a more conservative manner.
However, tumour-specific factors are not the only factors influencing postoperative survival. One major influencing variable is the physical condition of the patient. A prospective study by Yeoh and Fazal revealed a significant positive correlation between a higher ASA status and the length of hospital stay, which resulted in a higher 30-day mortality. Furthermore, smoking, a well-known risk factor for the development of OSCC, also influences the postoperative survival time. A review of the literature has shown that long-term smoking is significantly correlated with a decreased survival time and poorer overall outcome compared with the never-having-smoked status. However, contradictory reports stating no influence on survival time can also be found.
The purpose of this study was to identify tumour-specific and patient-related risk factors in a large single-centre cohort, i.e., factors that have a significant influence on postoperative survival following ablative tumour surgery with elective neck dissection and immediate microvascular reconstruction of OSCC.
Methods
Ethical statement and patient recruitment
All clinical investigations and procedures were conducted according to the principles expressed in the Declaration of Helsinki. Written patient consent was obtained. Every patient gave informed consent to participate in the clinical study with regard to the analysis of survival and outcomes of therapy. Exemption from the requirement of ethical approval was granted by the Ethics Committee of the Technische Universität München based on informed consent to participate in the study and on the patients’ willingness to undergo the required medical care.
The cases of all patients with OSCC treated surgically between 2007 and 2013 in the Department of Oral and Maxillofacial Surgery of Klinikum rechts der Isar in Munich, Germany, were assessed for inclusion in this retrospective study. Patients undergoing biopsies, diagnostic operations (e.g., panendoscopy), and cases with recurrent or multifocal OSCC were not included in this study. To exclude the potential bias of an inhomogeneous group due to the different extents of surgery and magnitudes of invasion (T stage) of the OSCC, only patients reconstructed with free flaps were included in this study. Only patients who underwent immediate microvascular reconstruction with one of the three common flaps – radial forearm flap, fibula flap, and anterolateral thigh (ALT) flap – were included ( Fig. 1 ). No further exclusion criteria were applied.
Staging
All patients underwent incisional biopsy, computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck, and chest radiography.
Postoperative histopathological assessment by pathologists was used as the diagnostic gold standard, and each case was discussed again by the interdisciplinary tumour board with respect to adjuvant therapy versus close follow-up.
Surgery and follow-up
All patients received an elective, ipsilateral neck dissection of levels I–III. Further escalation with neck dissection of levels IV and V ipsilaterally and of I–III contralaterally was performed if necessary, depending on the location of metastases discerned intraoperatively in frozen sections. Every patient included in this retrospective analysis underwent immediate reconstruction with the use of a microvascular radial forearm flap, fibula flap, or ALT flap, depending on the defect resulting from radical ablative tumour resection. The tumour resection with a minimum of 5-mm free/safe margins in all dimensions and the immediate microsurgical reconstruction were performed in accordance with current guidelines, as described previously. The decision whether to perform adjuvant therapy or not was made by the interdisciplinary tumour board. Adjuvant therapy was recommended in cases of ≥T3, N1–3, cases in which the presence of residual tumour could not be evaluated (Rx), and cases with microscopic or macroscopic residual tumour (R1–2) with radiation therapy alone. In cases of extracapsular invasion, additional chemotherapy (fluorouracil and cisplatin) was administered. In cases of N1 without extracapsular invasion, radiation therapy was recommended if the tumour showed further characteristics such as involvement of perineurial invasion (Pn >1 ) and grade 3 (G3). Patients were informed of the treatment options in such cases and made the decision (informed consent).
All patients were invited to special consultation appointments and were assessed every 3 months for the first 3 years postoperative and every 6 months for the following 2 years. In the case of an uneventful follow-up lasting 5 years, the patient was withdrawn from the consultation appointments.
Statistical methods
Study data were collected retrospectively in a single department. Kaplan–Meier curves were used to compare postoperative survival between the various factor groups. Univariate and multivariate Cox proportional hazards regression was used to assess the univariate and independent effects of each predictor on survival. All significant univariate predictors were included in the multivariate model. All statistical tests were performed at the 0.05 statistical level. P -values were two-sided and subjected to a global significance level of 0.05. For the analysis of tumour location, this was grouped as tongue, mandible, floor of mouth, buccal mucosa, maxilla and palate. Cases with N stages N2 and N3 were merged. The data were analyzed using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY, USA).
Results
General characteristics
A total of 695 patients were initially identified for inclusion in this study. After applying the study inclusion and exclusion criteria, 420 consecutive patients with primary OSCC were eligible for the study ( Fig. 1 ). Survival time data were available for 392 patients with histopathological stage T1–4 OSCC of the oral cavity. These patients made up the study sample for further analysis. Definitive T stage data were available for all 392 cases: 105 were T1 (26.8%), 123 were T2 (31.4%), 50 were T3 (12.7%), and 114 were T4 (29.1%) ( Table 1 ).
| Characteristics | All patients, n (%) |
|---|---|
| T stage | |
| 1 | 105 (26.8%) |
| 2 | 123 (31.4%) |
| 3 | 50 (12.7%) |
| 4 | 114 (29.1%) |
| N stage | |
| 0 | 244 (62.2%) |
| 1 | 49 (12.5%) |
| 2 | 96 (24.5%) |
| 3 | 3 (0.8%) |
| UICC stage | |
| 1 | 86 (21.9%) |
| 2 | 73 (18.6%) |
| 3 | 64 (16.3%) |
| 4 | 169 (43.1%) |
| Tumour grade | |
| 1 | 44 (11.2%) |
| 2 | 252 (64.3%) |
| 3 | 96 (24.5%) |
| Localization | |
| Tongue | 94 (24.0%) |
| Floor of the mouth | 145 (37.0%) |
| Lower jaw | 75 (19.1%) |
| Upper jaw | 20 (5.1%) |
| Buccal site | 32 (8.2%) |
| Soft palate | 26 (6.6%) |
| Surgery time | |
| ≤400 min | 42 (10.7%) |
| >400 min | 350 (89.3%) |
| ≤500 min | 147 (37.5%) |
| >500 min | 245 (62.5%) |
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